Etanercept therapy for toxic epidermal necrolysis Andrea Paradisi, MD,a Damiano Abeni, MD,a Fabio Bergamo, MD,b Francesco Ricci, MD,c Dario Didona, MD,d and Biagio Didona, MDb Rome, Italy Background: Toxic epidermal necrolysis (TEN) is a severe and potentially lethal drug reaction for which no standard treatment is available. Objective: To describe a case series of patients with TEN treated with a single dose of etanercept. Methods: We observed 10 consecutive patients with TEN. For each patient, we recorded the presence of comorbidities and all the drugs recently started (ie, in the last month). In all cases, 50 mg of etanercept was administered in a single subcutaneous injection. The clinical severity of disease was computed using the SCORe of Toxic Epidermal Necrosis (SCORTEN) scale. Using the probabilities of death linked to each level of SCORTEN score, we calculated the expected probability of death in our patients. Healing was defined as complete reepithelialization, and a time to healing curve was then obtained using the KaplaneMeier method. Results: All patients promptly responded to treatment, reaching complete reepithelialization without complications or side effects. The median time to healing was 8.5 days. Limitations: This is a small, uncontrolled case series. Conclusion: These preliminary results suggest the possibility that tumor necrosis factorealfa may be an effective target for control of TEN, a dangerous skin condition for which no effective cure has yet been found. ( J Am Acad Dermatol 2014;71:278-83.) Key words: adverse drug reaction; etanercept; therapy; toxic epidermal necrolysis.
oxic epidermal necrolysis (TEN), also known as Lyell syndrome, is a severe adverse drug reaction that is characterized by extensive skin necrosis and detachment of the epidermis and mucous membranes.1 TEN is considered a medical emergency; its estimated incidence is 0.4 to 1.2 cases per million persons per year, and mortality rates range from 25% to 35%.2-4 Early symptoms can be nonspecific (eg, fever, stinging eyes, and dysphagia) and are followed by a widespread erythematous rash and livid macules that have a tendency to coalescence rapidly. In the next phase, symptoms include flaccid bullae, epidermal detachment over large
T
areas ([30% of the body surface area [BSA]), and painful hemorrhagic erosions of the mucous membranes in[90% of patients.5 TEN is an idisiosyncratic drug reaction: allopurinol, antibiotics, anticonvulsants, and nonsteroidal antiinflammatory drugs seem to be the most common triggers.6 No treatment— including systemic steroids,7 which have been the standard therapy for TEN for about 20 years—has yet been shown to be effective in controlled clinical trials. Recently, encouraging but sporadic results of treatment with tumor necrosis factorealfa (TNF-a) antagonists have been described in the international literature.8-18
From the Health Services Research Unita and the I Division of Dermatology,b IDI-IRCCS, and the Departments of Dermatology, Catholic University of the Sacred Heartc and ‘‘La Sapienza’’ University,d Rome. Supported in part by the ‘‘Progetto Ricerca Corrente 2014’’ given by the Italian Ministry of Health to the Health Services Research Unit of the IDI-IRCCS, Rome, Italy (grant number Progetto Ricerca Corrente 2012: 5.3 [Strumenti e misure per la descrizione e la valutazione della gravita delle malattie dermatologiche]).
Conflicts of interest: None declared. Accepted for publication April 15, 2014. Correspondence to: Andrea Paradisi, MD, Health Services Research Unit, IDI-IRCCS, Via dei Monti di Creta 104, 00168 Rome, Italy. E-mail: [email protected]. Published online June 10, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.04.044
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The aim of this study was to evaluate the efficacy and safety of etanercept in a series of TEN patients.
were usually referred to our center within 72 hours of symptom onset. The clinical severity of disease was computed using the SCORe of Toxic Epidermal Necrosis METHODS (SCORTEN) scale.19 The scale ranges from 0 to 7 We observed 10 consecutive patients who were and attributes 1 point for the presence of each of the hospitalized with TEN at the IDI-IRCCS dermatologic following 7 items: age [40 years; heart rate [120 institute in Rome, Italy, between 2011 and 2012. We beats per minute; the presobtained written informed ence of malignancies; BSA consent from all patients for CAPSULE SUMMARY involvment [10%; serum treatment with etanercept. urea [10 mmol/L; serum biThe compassionate use of Toxic epidermal necrolysis is a severe, carbonate \20 mmol/L; and etanercept for TEN had potentially lethal drug reaction for which serum glucose [14 mmol/L. been approved by the no effective cure has yet been found. Using the probabilities of Ethical Committee of the Ten patients with toxic epidermal death linked to each level of IDI-IRCCS. necrolysis treated with a single dose of SCORTEN score, published On admission, when a etanercept (50 mg) showed complete in the original validation diagnosis of TEN was hyhealing without complications or side study, we calculated the pothesized, information on effects. expected probability of all probable causative medideath in our patients. cations was collected, and Tumor necrosis factorealfa may be an Healing was defined as such treatments were immeeffective new therapeutic approach for complete reepithelialization diately stopped. toxic epidermal necrolysis. (ie, the complete absence of All patients underwent the erosions), and time to healfollowing examinations: ing was recorded for each patient. A time to healing routine blood tests, immunologic tests (ie, antinucurve was then obtained using the KaplaneMeier clear antibodies, antieextractable nuclear antigen product-limit estimates method.20 antibodies, antiskin antibodies [ASA-IIF], antidesmogleins 1 and 3, anti-BPs 180 and 230, serology for RESULTS hepatitis C and B viruses, and HIV infection, The single components of the SCORTEN for each Quantiferon test), chest radiographs, electrocardiopatient are shown in Table I. Three patients were in graphy, and cardiologic evaluation. the higher category of SCORTEN severity (ie, a score For each patient, we recorded the presence of $ 5), while no patient was in the lower category comorbidities and all of the drugs recently started (ie, a score of 0-1). (ie, in the last month). Other important charactersitics of the patients TEN was diagnosed clinically according to the (ie, sex, age, comorbidities, culprit drugs, and time following critera: denudation of the epidermis in sheets to healing) are summarized in Table II. during the acute phase, with blisters and erosions Nine patients presented with comorbidities, covering [30% of the BSA, often with a positive which were considered severe in 8 cases. Three Nikolsky sign.4 Moreover, other common clinical patients had malignancies: 2 had a primary cerebral features of TEN have been evaluated, such as painful neoplasm and 1 had a brain metastasis from inflammation and ulceration of the mucosal surfaces breast cancer. The drug most frequently involved in and ocular and genital involvement. When the clinical triggering TEN was carbamazepine, which is used to features were not clear-cut characteristics of TEN, the prevent epileptic seizures. suspected diagnosis was confirmed histologically. All patients promptly responded to treatment, All patients were given intravenous fluid reaching complete reepithelialization without comreplacement, aseptic handling, and nutritional supplications or side effects (Fig 1). The exact binomial port. However, given the great diversity of the 95% confidence interval for the observed proportion problems posed by each case, no standard of deaths (ie, 0) ranges from 0% to 30.8%, which approach was adopted; rather, supportive therapy does not contain the expected probability of death in was tailored to the needs of each patient. In all our sample, computed on the basis of patients’ cases, 50 mg of etanercept was administered in a SCORTEN scores (46.9%). single subcutaneous injection. All patients were Time to healing ranged from 7 to 20 days treated as soon as possible, and invariably within (median, 8.5 days). The KaplaneMeier curve for 6 hours from hospitalization. The time from all observations is shown in Fig 2. symptom onset is not known precisely, but patients d
d
d
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Intracranial Periarthritis Cerebral metastases hemorrhage (breast cancer) (head trauma) — Cerebral neoplasm
F, Female; M, male.
Bronchopneumonia
Systemic lupus Pemphigus vulgaris Bronchopneumonia erythematosus
9 9
10 9 8
M 71 Carbamazepine
Cerebral neoplasm
In our series of TEN patients treated with a single dose of etanercept, healing was obtained in all cases without severe side effects. Findings reporting increased levels of TNF-a in skin biopsy specimens21 or in blister fluid and serum22 of TEN patients encouraged the adoption of biologic therapy with antieTNF-a monoclonal antibodies (infliximab) or with a soluble fusion protein binding to human TNF-a (etanercept). Although reports of TEN managed with biologic agents are scarce, the present study confirms the reported effectiveness of antieTNA-a drugs.8-18 Only 2 patients with TEN treated with 2 doses of etanercept (25 mg/day on days 4 and 816 and at an interval of 1 day,17 respectively) have been described. In the first patient,16 who had previously been treated with corticosteroids without benefit, epidermal detachment ceased within 24 hours of the first dose. Unfortunately, he then died of disseminated intravascular coagulation 10 days after admission. The other patient17 was given corticosteroids both previously and simultaneously with etanercept, and epidermal detachment stopped 2 days after the first etanercept injection. A patient with acute generalized exanthematous pustulosis/TEN overlap syndrome18 was successfully treated with etanercept 25 mg (twice in a week), with disease arrest being achieved within 48 hours of the first injection. Although these case reports describe promising outcomes, none were controlled studies, and the overall patient number is still small. Nonetheless, such outcomes are much more favorable than those obtained with ‘‘standard’’ approaches.23-39
8
DISCUSSION
12
SCORTEN, SCORe of Toxic Epidermal Necrosis.
8
6 3 2 3 4 5 2 6 2 3
12
0 0 0 0 1 1 0 1 0 1
Time to healing (days) Comorbidities
1 0 0 0 0 0 0 1 0 0
7
1 1 0 0 0 0 0 1 0 0
6
1 1 1 1 1 1 1 1 1 1
M F F 78 72 50 Carbamazepine Phytotherapy Carbamazepine product 7 8 20
10
5
9
M 73 Ciprofloxacin
8
F 62 Methylprednisolone
7
F 28 Lansoprazole, azathioprine 8
6
M 70 Ofloxacin
5
Patient no.
4
4
3
3
2
2
1 1 0 1 1 1 1 1 1 1 1 0 1 1 1 1 0 0 0 0 1 0 0 0 0 1 0 1 0 0
1
1
Age [40 y Heart rate [120 beats/min Cancer or hematologic malignancy [10% body surface area involvement Serum urea level [10 mmol/L Serum bicarbonate level \20 mmol/L Serum glucose level [14 mmol/L SCORTEN score
Table II. Patients with toxic epidermal necrolysis treated with etanercept: Sex, age, comorbidities, culprit drugs, and time to healing
SCORTEN components
F 57 Carbamazepine
Patient no.
Gender Age, y Culprit drug
Table I. Detail of the SCORTEN components and SCORTEN scores in 10 patients with toxic epidermal necrolysis treated with etanercept
F 55 Diclofenac
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Fig 1. Two patients with toxic epidermal vecrolysis before (A and C) and after treatment with a 50 mg single-dose subcutaneous injection of etanercept (B and D), respectively.
The pathogenesis of TEN is unclear. The observations that TEN recurrence is faster and more severe if the patient is reexposed to the culprit drug40; that drug-specific T cells are found in the skin of TEN patients41; and that patients with certain human leukocyte antigen haplotypes are at a greater risk of developing TEN when exposed to certain drugs42,43 strongly support a role for T cellemediated immune responses in its pathogenesis. However, the immune cell infiltration (including cytotoxic T cells) found in the skin of TEN patients seems insufficient to induce massive keratinocyte apoptosis, suggesting that some cytotoxic proteins and/or cytokines may amplify the process. The upregulation of FasL expression on the surface of keratinocytes from TEN patients has been shown to induce keratinocyte apoptosis by engaging constitutively expressed Fas.44 A recent study45 has advanced the hypothesis of a link between the drug-specific immune response and the induction of target cell death by apoptotic molecules (including FasL) by positing a role for inducible nitric oxide synthase
(iNOS). iNOS is significantly increased in the epidermis of TEN patients,46 and in keratinocytes it is regulated by interferon-gamma and TNF-a, whose levels in blister fluid from TEN patients are increased.47,48 According to the aforementioned construct, an iNOS/nitric oxide/FasL pathway might link the immune activation and the widespread keratinocyte apoptosis seen in TEN: the authors45 noted that activated T cells secrete large amounts of TNF-a and interferon-gamma, which have the ability to induce iNOS expression and nitric oxide production by keratinocytes, resulting in FasL upregulation and Fas-mediated keratinocyte apoptosis. Etanercept therapy would act by blocking this inflammatory pathway via TNF-a inhibition. It is also noteworthy that etanercept, in addition to TNF-a, also blocks lymphotoxin a (LFT-a), which has been recently reported to play an important role in the pathogenesis of graft-versus-host disease,49 which shares clinical,50 histologic, and pathogenetic51,52 resemblances to TEN. We therefore believe that LFT-a could play a role in TEN pathogenesis,
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Fig 2. Kaplan-Meier curve for time to healing (days) in 10 patients with toxic epidermal necrolysis treated with Etanercept.
and its block, together with that of TNF-a, may be at least partially linked to the robust and rapid therapeutic effect of etanercept seen in our patients. The present study is small and lacks a control group. However, to the best of our knowledge, this is the largest series of TEN patients to have been treated with a biologic agent. Moreover, despite the small sample size, the upper 95% confidence interval for the 0 observed deaths (30.8%) is well below the expected probability of death computed in our sample on the basis of patients’ SCORTEN scores (46.9%). In addition, given the high expected probability of death among patients undergoing the ‘‘standard’’ treatments, it may actually be unethical to assign patients to a control group. The present study is also characterized by a number of advantages, because it was not only carried out at a single institution, but also in a single clinical unit; this entails that all patients were seen by the same dermatologists, observed in the same environmental conditions, and treated in a standardized manner consisting of a single dose of etanercept, while all other TEN medications were withdrawn. We hope that these results may encourage other clinicians to test this therapeutic approach, which may provide a breakthrough for a dangerous skin condition for which no effective cure has yet been found. We thank Moira Egan for editing the final version of the manuscript.
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REFERENCES 1. Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 1956;68:355-61. 2. Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 1990;23:1039-58. 3. Roujeau JC, Guillaume JC, Fabre JP, Penso D, Flechet ML, Girre JP. Toxic epidermal necrolysis (Lyell syndrome). Incidence and drug etiology in France, 1981-1985. Arch Dermatol 1990;126:37-42. 4. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis. Part I. J Am Acad Dermatol 2013;173:e1-13. 5. Harr T, French LE. Stevens-Johnson syndrome and toxic epidermal necrolysis. Chem Immunol Allergy 2012;97: 149-66. 6. Mockenhaupt M. Epidemiology of cutaneous adverse drug reactions. Chem Immunol Allergy 2012;97:1-17. 7. Fernando SL. The management of toxic epidermal necrolysis. Australas J Dermatol 2012;53:165-71. 8. Fischer M, Fiedler E, Marsch WC, Wohlrab J. Antitumour necrosis factor-alpha antibodies (infliximab) in the treatment of a patient with toxic epidermal necrolysis. Br J Dermatol 2002;146:707-9. 9. Hunger RE, Hunziker T, Buettiker U, Braathen LR, Yawalkar N. Rapid resolution of toxic epidermal necrolysis with anti-TNF-alpha treatment. J Allergy Clin Immunol 2005;116: 923-4. 10. Wojtkiewicz A, Wysocki M, Fortuna J, Chrupek M, Matczuk M, Koltan A. Beneficial and rapid effect of infliximab on the course of toxic epidermal necrolysis. Acta Derm Venereol 2008;88:420-1. 11. Kreft B, Wohlrab J, Bramsiepe I, Eismann R, Winkler M, Marsch WC. Etoricoxib-induced toxic epidermal necrolysis: successful treatment with infliximab. J Dermatol 2010;37:904-6. 12. Worsnop F, Wee J, Natkunarajah J, Moosa Y, Marsden R. Reaction to biological drugs: infliximab for the treatment of toxic epidermal necrolysis subsequently triggering erosive lichen planus. Clin Exp Dermatol 2012;37:879-81. 13. Al-Shouli S, Abouchala N, Bogusz MJ, Al Tufail M, ThestrupPedersen K. Toxic epidermal necrolysis associated with high intake of sildenafil and its response to infliximab. Acta Derm Venereol 2005;85:534-5. 14. Meiss F, Helmbold P, Meykadeh N, Gaber G, Marsch WC, Fischer M. Overlap of acute generalized exanthematous pustulosis and toxic epidermal necrolysis: response to antitumour necrosis factor-alpha antibody infliximab: report of three cases. J Eur Acad Dermatol Venereol 2007; 21:717-9. 15. Gaitanis G, Spyridonos P, Patmanidis K, Koulouras V, Nakos G, Tzaphlidou M, et al. Treatment of toxic epidermal necrolysis with the combination of infliximab and high-dose intravenous immunoglobulin. Dermatology 2012;224:134-9. 16. Famularo G, Di Dona B, Canzona F, Girardelli CR, Cruciani G. Etanercept for toxic epidermal necrolysis. Ann Pharmacother 2007;41:1083-4. 17. Gubinelli E, Canzona F, Tonanzi T, Raskovic D, Didona B. Toxic epidermal necrolysis successfully treated with etanercept. J Dermatol 2009;36:150-3. 18. Sadighha A. Etanercept in the treatment of a patient with acute generalized exanthematous pustulosis/toxic epidermal necrolysis: definition of a new model based on translational research. Int J Dermatol 2009;48:913-4. 19. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149-53.
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20. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. 21. Paquet P, Paquet F, Al Saleh W, Reper P, Vanderkelen A, Pi erard GE. Immunoregulatory effector cells in drug-induced toxic epidermal necrolysis. Am J Dermatopathol 2000;22: 413-7. 22. Posadas SJ, Padial A, Torres MJ, Mayorga C, Leyva L, Sanchez E, et al. Delayed reactions to drugs show levels of perforin, granzyme B, and Fas-L to be related to disease severity. J Allergy Clin Immunol 2002;109:155-61. 23. Lee HY, Dunant A, Sekula P, Mockenhaupt M, Wolkenstein P, Valeyrie-Allanore L, et al. The role of prior corticosteroid use on the clinical course of Stevens-Johnson syndrome and toxic epidermal necrolysis: a case-control analysis of patients selected from the multinational EuroSCAR and RegiSCAR studies. Br J Dermatol 2012;167:555-62. 24. Yamane Y, Aihara M, Tatewaki S, Matsukura S, Kanbara T, Yamakawa Y, et al. Analysis of treatments and deceased cases of severe adverse drug reactions—analysis of 46 cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Arerugi 2009;58:537-47. 25. Mockenhaupt M. Severe drug-induced skin reactions: clinical pattern, diagnostics and therapy. J Dtsch Dermatol Ges 2009; 7:142-60. 26. Ghislain PD, Roujeau JC. Treatment of severe drug reactions: StevenseJohnson syndrome, toxic epidermal necrolysis and hypersensitivity syndrome. Dermatol Online J 2002;8:5. 27. Valeyrie-Allanore L, Wolkenstein P, Brochard L, Ortonne N, Ma^ıtre B, Revuz J, et al. Open trial of ciclosporin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol 2010;163:847-53. 28. Ballow M. The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders. J Allergy Clin Immunol 2011;127:315-23. 29. Campione E, Marulli GC, Carrozzo AM, Chimenti MS, Costanzo A, Bianchi L. High-dose intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venereol 2003;83:430-2. 30. Prins C, Vittorio C, Padilla RS, Hunziker T, Itin P, F€ orster J, et al. Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: a retrospective, multicenter study. Dermatology 2003;207:96-9. 31. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Use of SCORTEN to accurately predict mortality in patients with toxic epidermal necrolysis in the United States. Arch Dermatol 2004;140:890-2. 32. French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding. Int Immunopharmacol 2006;6:543-9. 33. Al-Mutairi N, Arun J, Osama NE, Amr Z, Mazen AS, Ibtesam el-A, et al. Prospective, noncomparative open study from Kuwait of the role of intravenous immunoglobulin in the treatment of toxic epidermal necrolysis. Int J Dermatol 2004; 43:847-51. 34. Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol 2008;58:33-40. 35. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic
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epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 2003;139:33-6. Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni A, Gamelli RL. Toxic epidermal necrolysis: does immunoglobulin make a difference? J Burn Care Rehabil 2004;25:81-8. Shortt R, Gomez M, Mittman N, Cartotto R. Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis. J Burn Care Rehabil 2004;25:246-55. Pasic S. Intravenous immunoglobulin in toxic epidermal necrolysis. Int J Dermatol 2006;45:1117-8. Faye O, Roujeau JC. Treatment of epidermal necrolysis with high-dose intravenous immunoglobulins (IV Ig): clinical experience to date. Drugs 2005;65:2085-90. Paquet P, Jacob E, Damas P, Pierard GE. Recurrent fatal drug-induced toxic epidermal necrolysis (Lyell’s syndrome) after putative beta-lactam cross-reactivity: case report and scrutiny of antibiotic imputability. Crit Care Med 2002;30: 2580-3. Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P, et al. Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol 2004;114:1209-15. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428:486. Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 2005;102:4134-9. Viard-Leveugle I, Bullani RR, Meda P, Micheau O, Limat A, Saurat JH, et al. Intracellular localization of keratinocyte Fas ligand explains lack of cytolytic activity under physiological conditions. J Biol Chem 2003;278:16183-8. Viard-Leveugle I, Gaide O, Jankovic D, Feldmeyer L, Kerl K, Pickard C, et al. TNF-a and IFN-g are potential inducers of Fas-mediated keratinocyte apoptosis through activation of inducible nitric oxide synthase in toxic epidermal necrolysis. J Invest Dermatol 2013;133:489-98. Lerner LH, Qureshi AA, Reddy BV, Lerner EA. Nitric oxide synthase in toxic epidermal necrolysis and Stevens-Johnson syndrome. J Invest Dermatol 2000;114:196-9. Nassif A, Moslehi H, Le Gouvello S, Bagot M, Lyonnet L, Michel L, et al. Evaluation of the potential role of cytokines in toxic epidermal necrolysis. J Invest Dermatol 2004;123:850-5. Gandhi M, Kowal-Vern A, An G, Hanumadass M. Blister fluid composition in a pediatric patient with toxic epidermal necrolysis. J Burn Care Res 2008;29:671-5. Markey KA, Burman AC, Banovic T, Kuns RD, Raffelt NC, Rowe V, et al. Soluble lymphotoxin is an important effector molecule in GVHD and GVL. Blood 2010;115:122-32. Villada G, Roujeau JC, Cordonnier C, Bagot M, Kuentz M, Wechsler J, et al. Toxic epidermal necrolysis after bone marrow transplantation: study of nine cases. J Am Acad Dermatol 1990;23(5 pt 1):870-5. Correia O, Delgado L, Ramos JP, Resende C, Torrinha JA. Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD81 lymphocyte involvement. Arch Dermatol 1993;129:466-8. French LE, Tschopp J. Fas-mediated cell death in toxic epidermal necrolysis and graft-versus-host disease: potential for therapeutic inhibition. Schweiz Med Wochenschr 2000; 130:1656-61.
oxic epidermal necrolysis (TEN), also known as Lyell syndrome, is a severe adverse drug reaction that is characterized by extensive skin necrosis and detachment of the epidermis and mucous membranes.1 TEN is considered a medical emergency; its estimated incidence is 0.4 to 1.2 cases per million persons per year, and mortality rates range from 25% to 35%.2-4 Early symptoms can be nonspecific (eg, fever, stinging eyes, and dysphagia) and are followed by a widespread erythematous rash and livid macules that have a tendency to coalescence rapidly. In the next phase, symptoms include flaccid bullae, epidermal detachment over large
T
areas ([30% of the body surface area [BSA]), and painful hemorrhagic erosions of the mucous membranes in[90% of patients.5 TEN is an idisiosyncratic drug reaction: allopurinol, antibiotics, anticonvulsants, and nonsteroidal antiinflammatory drugs seem to be the most common triggers.6 No treatment— including systemic steroids,7 which have been the standard therapy for TEN for about 20 years—has yet been shown to be effective in controlled clinical trials. Recently, encouraging but sporadic results of treatment with tumor necrosis factorealfa (TNF-a) antagonists have been described in the international literature.8-18
From the Health Services Research Unita and the I Division of Dermatology,b IDI-IRCCS, and the Departments of Dermatology, Catholic University of the Sacred Heartc and ‘‘La Sapienza’’ University,d Rome. Supported in part by the ‘‘Progetto Ricerca Corrente 2014’’ given by the Italian Ministry of Health to the Health Services Research Unit of the IDI-IRCCS, Rome, Italy (grant number Progetto Ricerca Corrente 2012: 5.3 [Strumenti e misure per la descrizione e la valutazione della gravita delle malattie dermatologiche]).
Conflicts of interest: None declared. Accepted for publication April 15, 2014. Correspondence to: Andrea Paradisi, MD, Health Services Research Unit, IDI-IRCCS, Via dei Monti di Creta 104, 00168 Rome, Italy. E-mail: [email protected]. Published online June 10, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.04.044
278
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Paradisi et al 279
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The aim of this study was to evaluate the efficacy and safety of etanercept in a series of TEN patients.
were usually referred to our center within 72 hours of symptom onset. The clinical severity of disease was computed using the SCORe of Toxic Epidermal Necrosis METHODS (SCORTEN) scale.19 The scale ranges from 0 to 7 We observed 10 consecutive patients who were and attributes 1 point for the presence of each of the hospitalized with TEN at the IDI-IRCCS dermatologic following 7 items: age [40 years; heart rate [120 institute in Rome, Italy, between 2011 and 2012. We beats per minute; the presobtained written informed ence of malignancies; BSA consent from all patients for CAPSULE SUMMARY involvment [10%; serum treatment with etanercept. urea [10 mmol/L; serum biThe compassionate use of Toxic epidermal necrolysis is a severe, carbonate \20 mmol/L; and etanercept for TEN had potentially lethal drug reaction for which serum glucose [14 mmol/L. been approved by the no effective cure has yet been found. Using the probabilities of Ethical Committee of the Ten patients with toxic epidermal death linked to each level of IDI-IRCCS. necrolysis treated with a single dose of SCORTEN score, published On admission, when a etanercept (50 mg) showed complete in the original validation diagnosis of TEN was hyhealing without complications or side study, we calculated the pothesized, information on effects. expected probability of all probable causative medideath in our patients. cations was collected, and Tumor necrosis factorealfa may be an Healing was defined as such treatments were immeeffective new therapeutic approach for complete reepithelialization diately stopped. toxic epidermal necrolysis. (ie, the complete absence of All patients underwent the erosions), and time to healfollowing examinations: ing was recorded for each patient. A time to healing routine blood tests, immunologic tests (ie, antinucurve was then obtained using the KaplaneMeier clear antibodies, antieextractable nuclear antigen product-limit estimates method.20 antibodies, antiskin antibodies [ASA-IIF], antidesmogleins 1 and 3, anti-BPs 180 and 230, serology for RESULTS hepatitis C and B viruses, and HIV infection, The single components of the SCORTEN for each Quantiferon test), chest radiographs, electrocardiopatient are shown in Table I. Three patients were in graphy, and cardiologic evaluation. the higher category of SCORTEN severity (ie, a score For each patient, we recorded the presence of $ 5), while no patient was in the lower category comorbidities and all of the drugs recently started (ie, a score of 0-1). (ie, in the last month). Other important charactersitics of the patients TEN was diagnosed clinically according to the (ie, sex, age, comorbidities, culprit drugs, and time following critera: denudation of the epidermis in sheets to healing) are summarized in Table II. during the acute phase, with blisters and erosions Nine patients presented with comorbidities, covering [30% of the BSA, often with a positive which were considered severe in 8 cases. Three Nikolsky sign.4 Moreover, other common clinical patients had malignancies: 2 had a primary cerebral features of TEN have been evaluated, such as painful neoplasm and 1 had a brain metastasis from inflammation and ulceration of the mucosal surfaces breast cancer. The drug most frequently involved in and ocular and genital involvement. When the clinical triggering TEN was carbamazepine, which is used to features were not clear-cut characteristics of TEN, the prevent epileptic seizures. suspected diagnosis was confirmed histologically. All patients promptly responded to treatment, All patients were given intravenous fluid reaching complete reepithelialization without comreplacement, aseptic handling, and nutritional supplications or side effects (Fig 1). The exact binomial port. However, given the great diversity of the 95% confidence interval for the observed proportion problems posed by each case, no standard of deaths (ie, 0) ranges from 0% to 30.8%, which approach was adopted; rather, supportive therapy does not contain the expected probability of death in was tailored to the needs of each patient. In all our sample, computed on the basis of patients’ cases, 50 mg of etanercept was administered in a SCORTEN scores (46.9%). single subcutaneous injection. All patients were Time to healing ranged from 7 to 20 days treated as soon as possible, and invariably within (median, 8.5 days). The KaplaneMeier curve for 6 hours from hospitalization. The time from all observations is shown in Fig 2. symptom onset is not known precisely, but patients d
d
d
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280 Paradisi et al
Intracranial Periarthritis Cerebral metastases hemorrhage (breast cancer) (head trauma) — Cerebral neoplasm
F, Female; M, male.
Bronchopneumonia
Systemic lupus Pemphigus vulgaris Bronchopneumonia erythematosus
9 9
10 9 8
M 71 Carbamazepine
Cerebral neoplasm
In our series of TEN patients treated with a single dose of etanercept, healing was obtained in all cases without severe side effects. Findings reporting increased levels of TNF-a in skin biopsy specimens21 or in blister fluid and serum22 of TEN patients encouraged the adoption of biologic therapy with antieTNF-a monoclonal antibodies (infliximab) or with a soluble fusion protein binding to human TNF-a (etanercept). Although reports of TEN managed with biologic agents are scarce, the present study confirms the reported effectiveness of antieTNA-a drugs.8-18 Only 2 patients with TEN treated with 2 doses of etanercept (25 mg/day on days 4 and 816 and at an interval of 1 day,17 respectively) have been described. In the first patient,16 who had previously been treated with corticosteroids without benefit, epidermal detachment ceased within 24 hours of the first dose. Unfortunately, he then died of disseminated intravascular coagulation 10 days after admission. The other patient17 was given corticosteroids both previously and simultaneously with etanercept, and epidermal detachment stopped 2 days after the first etanercept injection. A patient with acute generalized exanthematous pustulosis/TEN overlap syndrome18 was successfully treated with etanercept 25 mg (twice in a week), with disease arrest being achieved within 48 hours of the first injection. Although these case reports describe promising outcomes, none were controlled studies, and the overall patient number is still small. Nonetheless, such outcomes are much more favorable than those obtained with ‘‘standard’’ approaches.23-39
8
DISCUSSION
12
SCORTEN, SCORe of Toxic Epidermal Necrosis.
8
6 3 2 3 4 5 2 6 2 3
12
0 0 0 0 1 1 0 1 0 1
Time to healing (days) Comorbidities
1 0 0 0 0 0 0 1 0 0
7
1 1 0 0 0 0 0 1 0 0
6
1 1 1 1 1 1 1 1 1 1
M F F 78 72 50 Carbamazepine Phytotherapy Carbamazepine product 7 8 20
10
5
9
M 73 Ciprofloxacin
8
F 62 Methylprednisolone
7
F 28 Lansoprazole, azathioprine 8
6
M 70 Ofloxacin
5
Patient no.
4
4
3
3
2
2
1 1 0 1 1 1 1 1 1 1 1 0 1 1 1 1 0 0 0 0 1 0 0 0 0 1 0 1 0 0
1
1
Age [40 y Heart rate [120 beats/min Cancer or hematologic malignancy [10% body surface area involvement Serum urea level [10 mmol/L Serum bicarbonate level \20 mmol/L Serum glucose level [14 mmol/L SCORTEN score
Table II. Patients with toxic epidermal necrolysis treated with etanercept: Sex, age, comorbidities, culprit drugs, and time to healing
SCORTEN components
F 57 Carbamazepine
Patient no.
Gender Age, y Culprit drug
Table I. Detail of the SCORTEN components and SCORTEN scores in 10 patients with toxic epidermal necrolysis treated with etanercept
F 55 Diclofenac
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Fig 1. Two patients with toxic epidermal vecrolysis before (A and C) and after treatment with a 50 mg single-dose subcutaneous injection of etanercept (B and D), respectively.
The pathogenesis of TEN is unclear. The observations that TEN recurrence is faster and more severe if the patient is reexposed to the culprit drug40; that drug-specific T cells are found in the skin of TEN patients41; and that patients with certain human leukocyte antigen haplotypes are at a greater risk of developing TEN when exposed to certain drugs42,43 strongly support a role for T cellemediated immune responses in its pathogenesis. However, the immune cell infiltration (including cytotoxic T cells) found in the skin of TEN patients seems insufficient to induce massive keratinocyte apoptosis, suggesting that some cytotoxic proteins and/or cytokines may amplify the process. The upregulation of FasL expression on the surface of keratinocytes from TEN patients has been shown to induce keratinocyte apoptosis by engaging constitutively expressed Fas.44 A recent study45 has advanced the hypothesis of a link between the drug-specific immune response and the induction of target cell death by apoptotic molecules (including FasL) by positing a role for inducible nitric oxide synthase
(iNOS). iNOS is significantly increased in the epidermis of TEN patients,46 and in keratinocytes it is regulated by interferon-gamma and TNF-a, whose levels in blister fluid from TEN patients are increased.47,48 According to the aforementioned construct, an iNOS/nitric oxide/FasL pathway might link the immune activation and the widespread keratinocyte apoptosis seen in TEN: the authors45 noted that activated T cells secrete large amounts of TNF-a and interferon-gamma, which have the ability to induce iNOS expression and nitric oxide production by keratinocytes, resulting in FasL upregulation and Fas-mediated keratinocyte apoptosis. Etanercept therapy would act by blocking this inflammatory pathway via TNF-a inhibition. It is also noteworthy that etanercept, in addition to TNF-a, also blocks lymphotoxin a (LFT-a), which has been recently reported to play an important role in the pathogenesis of graft-versus-host disease,49 which shares clinical,50 histologic, and pathogenetic51,52 resemblances to TEN. We therefore believe that LFT-a could play a role in TEN pathogenesis,
282 Paradisi et al
Fig 2. Kaplan-Meier curve for time to healing (days) in 10 patients with toxic epidermal necrolysis treated with Etanercept.
and its block, together with that of TNF-a, may be at least partially linked to the robust and rapid therapeutic effect of etanercept seen in our patients. The present study is small and lacks a control group. However, to the best of our knowledge, this is the largest series of TEN patients to have been treated with a biologic agent. Moreover, despite the small sample size, the upper 95% confidence interval for the 0 observed deaths (30.8%) is well below the expected probability of death computed in our sample on the basis of patients’ SCORTEN scores (46.9%). In addition, given the high expected probability of death among patients undergoing the ‘‘standard’’ treatments, it may actually be unethical to assign patients to a control group. The present study is also characterized by a number of advantages, because it was not only carried out at a single institution, but also in a single clinical unit; this entails that all patients were seen by the same dermatologists, observed in the same environmental conditions, and treated in a standardized manner consisting of a single dose of etanercept, while all other TEN medications were withdrawn. We hope that these results may encourage other clinicians to test this therapeutic approach, which may provide a breakthrough for a dangerous skin condition for which no effective cure has yet been found. We thank Moira Egan for editing the final version of the manuscript.
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